The prognosis for patients with glioblastoma multiforme (GBM) has improved only slightly over the last few decades. Randomized trials have shown that radiotherapy improves outcomes (Walker et al., 1980, N. Eng. J. Med. 303:1323-9) and results in a median survival of 12 months (Curran, et al., 1993, J. Natl. Cancer Inst. 85:704-10; Scott, et al., 1998, Int. J. Radiat. Oncol. Biol. Phys. 40:51-5). A recent prospective clinical trial found that radiotherapy combined with temozolomide significantly improved survival, albeit by a modest 2.5 months (Stupp, et al., 2002, N. Eng. J. Med. 352:987-96). Attempts have been made at increasing the radiation dose either with additional external beam radiotherapy (Chan, et al., 2002, J. Clin. Oncol. 20:1635-42), brachytherapy (Tatter, et al., 2003, J. Neurosurg. 99:297-303), or stereotactic radiosurgery (Regine, et al., 2000, J. Radiat. Oncol. Biol. Phys. 48:421-6), but no significant improvement in survival has been demonstrated. Thus, an agent which preferentially enhances the cytotoxic effects of radiation on glioma cells, but has minimal effects on the survival of normal brain cells, has the potential to improve the therapeutic result for these patients (Steel et al., 1979, J. Radiat. Oncol. Biol. Phys. 5:85-91).
The major cellular pathways leading to sensing and repairing radiation-induced damage have been extensively studied, and the mechanisms involved have become attractive targets for agents that have the potential to increase therapeutic gain when combined with IR. This approach has identified some promising candidates (Li, et al., 2003, Nucleic Acids Res. 31:5848-57; Smart, et al., 2004, Cancer Res. 64:6716-24; Zhao, et al., 2006, Cancer Res. 66:5354-62) which are currently being investigated at the preclinical stage.
There exists in the art a need for novel radiosensitizing compounds. There also exists in the art a need for novel methods of treatment of cancers which exploit radiosensitizing compounds. Further, there exists a need in the art for a method of rapidly screening and identifying novel radiosensitizing compounds. The present invention fills these needs.